U.S. patent number 6,090,081 [Application Number 09/081,644] was granted by the patent office on 2000-07-18 for sealing stopper for a syringe and a prefilled syringe.
This patent grant is currently assigned to Daikyo Seiko, Ltd.. Invention is credited to Tomoyasu Muraki, Masamichi Sudo.
United States Patent |
6,090,081 |
Sudo , et al. |
July 18, 2000 |
Sealing stopper for a syringe and a prefilled syringe
Abstract
There can be provided a sealing stopper for a syringe, having
very high sealing property and sliding property, and a prefilled
syringe using this sealing stopper and capable of preserving a
medicament for a long time and operating in easy and precise manner
during injecting. This syringe is also excellent in sanitary and
operating property during a step of formulation or preservation of
a medicament. In this sealing stopper for a syringe, a surface of
the rubber body is laminated with a tetrafluoroethylene resin film
or ultra-high molecular weight polyethylene film having an average
roughness Ra on the central line of the surface in a range of at
most 0.05 .mu.m and a kinematic friction coefficient of at most
0.2.
Inventors: |
Sudo; Masamichi (Tokyo,
JP), Muraki; Tomoyasu (Tokyo, JP) |
Assignee: |
Daikyo Seiko, Ltd. (Tokyo,
JP)
|
Family
ID: |
15078007 |
Appl.
No.: |
09/081,644 |
Filed: |
May 20, 1998 |
Foreign Application Priority Data
|
|
|
|
|
May 22, 1997 [JP] |
|
|
9-132297 |
|
Current U.S.
Class: |
604/230;
604/218 |
Current CPC
Class: |
A61M
5/31513 (20130101); B29C 39/20 (20130101); A61M
2205/0222 (20130101); A61M 2205/0238 (20130101); B29L
2031/7544 (20130101); B29K 2027/18 (20130101); B29K
2995/0073 (20130101); A61M 2207/00 (20130101) |
Current International
Class: |
A61M
5/315 (20060101); B29C 39/00 (20060101); B29C
39/20 (20060101); A61M 005/315 () |
Field of
Search: |
;604/230,218,187 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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|
|
|
|
|
0 338 671 |
|
Oct 1989 |
|
EP |
|
0 528 529 |
|
Feb 1993 |
|
EP |
|
0 743 072 |
|
Nov 1996 |
|
EP |
|
48-8990 |
|
Jan 1973 |
|
JP |
|
62-139668 |
|
Jun 1987 |
|
JP |
|
63-97173 |
|
Apr 1988 |
|
JP |
|
1-138454 |
|
Sep 1989 |
|
JP |
|
1-138455 |
|
Sep 1989 |
|
JP |
|
5-293159 |
|
Sep 1993 |
|
JP |
|
Other References
Cf. "Plastic No Jiten (Plastic Dictionary)", pp. 836-838, published
by Asakura Shoten, Mar. 1, 1992. .
Japanese Pharmacopoeia Thirteenth Edition, pp. 9-27..
|
Primary Examiner: Yasko; John D.
Attorney, Agent or Firm: Wenderoth, Lind & Ponack,
L.L.P.
Claims
What is claimed is:
1. A sealing stopper for a syringe, comprising a rubber body
laminated with a tetrafluoroethylene resin film or ultra-high
molecular weight polyethylene film having an average roughness Ra
on the central line of a surface of said resin film or said
poluethylene film in a range of at most 0.05 .mu.m and a kinematic
friction coefficient of at most 0.2.
2. A sealing stopper for a syringe, as claimed in claim 1, wherein
the tetrafluoroethylene resin film is prepared by a casting-shaping
method comprising using, as a raw material, a suspension containing
tetrafluoroethylene resin powder having a grain diameter of at most
0.01 to 1.0 .mu.m, a dispersing agent and a solvent.
3. The sealing stopper for a syringe, as claimed in claim 1,
wherein said ultra-high molecular weight polyethylene film is
prepared by an inflation shaping method or an extrusion shaping
method.
4. A prefilled syringe, comprising an injection cylinder or
two-component cylinder for enclosing or sealing a medicament, the
medicament being enclosed or sealed by a sealing stopper for a
syringe having a rubber body laminated with a tetrafluoroethylene
resin film or ultrahigh molecular weight polyethylene film having
an average roughness Ra on the central
line of a surface of said resin film or said polyethylene film in a
range of at most 0.05 .mu.m and a kinematic friction coefficient of
at most 0.2.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a sealing stopper for a syringe and a
prefilled syringe consisting of an injection cylinder or
two-component cylinder in which a medicament is sealed by the use
of the sealing stopper for a syringe.
2. Description of the Prior Art
An injection agent as one agent form of a medicament includes a
solid formulation to be dissolved in administering and a liquid
formulation prepared in the form of a solution. As a means for
administering an injection agent in the body, there are a method
comprising directly administering a medicament liquid in the body
from a syringe and a method comprising mixing an injection agent
with another medicament liquid held by another container just
before administering and then introducing the mixture into the body
through an administering system, for example, another medical
instrument than syringes, such as drip injection set.
In the so-called prefilled syringe, an injection agent is
previously filled in an injection cylinder-cum-container,
transported or kept in custody, while sealing the end thereof by a
sealing stopper. For the adminisration of the injection agent, an
injection needle or administration device is fitted to the pointed
end, after which the sealing stopper is thrust toward the pointed
end and slidably moved to allow the injection agent to flow out of
the injection needle side and administer it. This syringe of
prefilled type has various advantages that 1 operation thereof is
very simple, 2 administration of a medicament is feasible with a
correct administration quantity without misuse of a medicament even
in case of emergency and 3 removal of a medicament is not required
to prevent the medicament from contamination with microorganisms
and to maintain highly sanitary conditions. Thus, the syringe of
prefilled type has lately been used often so as to improve the
efficiency of medical treatment in the actual medical scene and to
prevent contamination with microorganisms. Further, it has been
recommended to use a so-called kit article consisting of a system
of a solid agent, water for dissolving the solid agent and a
medicament liquid, in combination, because of the same reason.
Such a prefilled syringe is convenient as described above, but when
a medicament is kept in custody, high sealing property is required
and simultaneously, slidable movement of a sealing stopper is
required in administering. Namely, the prefilled syringe must have
a function of opposite properties, that is, sealing property and
slidable property.
In syringes of the prior art, silicone oils have been coated onto a
piston to unite both the sealing property and slidable property. Of
late, however, there arise problems, for example, lowering of the
potency due to adsorption of effective components of a medicament
on the silicone oil, contamination of a medicament with fine grains
as a stripped product of a silicone oil and bad influences upon the
human body thereby (poisonous character of silicone oil).
Accordingly, there is a late tendency of avoiding use of silicone
oils.
On the other hand, a movable sealing rubber stopper (which will
hereinafter be referred to as "sealing stopper" in some cases)
whose main body consists of a rubber has hitherto been known.
Examples include one having a fluoro resin film such as
tetrafluoroethylene laminated on the surface to be contacted with a
medicament liquid (Japanese Utility Model Publication No.
8990/1973), a sealing rubber stopper for and a prefilled syringe
having a polypropylene resin film laminated on all sites to be
contacted with an inner surface of a syringe (U.S. Pat. No.
4,554,125), etc.
Under the situation, the inventors have developed and proposed
syringes or two-component syringes capable of satisfying both the
sealing property and slidable property without using silicone oils
and having high sanitary and safety property. Examples include a
sealing stopper whose surface is coated with a
tetrafluoroethylene-ethylene copolymer resin (which will
hereinafter be referred to as "ETFE" in some cases), as disclosed
in Japanese Patent Laid-Open Publication No. 139668/1987, a sealing
stopper whose surface is coated with a polytetrafluoroethylene
resin film (which will hereinafter be referred to as "PTFE" in some
cases), as disclosed in Japanese Patent Laid-Open Publication No.
97173/1988, and a sealing stopper laminated with PTFE, ETFE or
ultrahigh molecular polyethylene resin film having a shape suitable
for a prefilled syringe, as disclosed in Japanese Utility Model
Laid-Open Publication No. 138454/1989 or 138455/1989. Furthermore,
there has been proposed a syringe consisting of a cyclic olefin
plastic capable of satisfying both the sealing property and
slidable property in combination with the sealing stopper as
described above, as disclosed in Japanese Patent Laid-Open
Publication No. 293159/1993.
In the general formulation provisions of the Japanese Pharmacopoeia
of 13th Revision, it is provided that a container for an injection
agent must be a hermetic container and the hermetic container is
defined as a container capable of daily handling and preventing a
medicament from being contaminated with gases or microorganisms
during ordinary storage.
Considering the prior art in view of this official provision, the
resin film-laminated sealing stopper has a large effect on
inhibition of dissolving-out of a rubber component of the stopper
body, but the sealing property tends to be lowered because of not
using silicone oil.
In the above described sealing stopper the inventors have
developed, it is necessary in order to maintain a sufficientsealing
property to design so that a difference between the outer diameter
of the sealing stopper and the inner diameter of the syringe is
somewhat large. Consequently, there arises a problem that the
sliding resistance during administering a medicament is somewhat
increased.
On the other hand, the inventors have made various studies about
resins to be laminated on surfaces of sealing stoppers and
consequently, have reached a conclusion that PTFE is most suitable,
and that high molecular weight polyethylene (which will hereinafter
be referred to as "UHMWPE" some times) is preferably used in
addition to fluoro resins, as compared with other fluoro resins.
Examples include tetrafluoroethylene-perfluoroethylenc copolymer
(PFA), tetrafluoroethylenene-hexafluoropropylene copolymer (FEP),
tetrafluoroethylene-ethylene copolymer (ETFE),
trichlorotrifluoroethylene (PCTFE), polyvinylidene fluoride (PVDF),
polyvinyl fluoride (PVF), etc. The reasons therefor will be
illustrated below.
The above described other fluoro resins can be subjected to thermal
melt molding, for example, injection molding or extrusion molding,
but PTFE having a melt flow rate (MFR) of substantially zero at its
melting point of 327.degree. C. and being non-sticky cannot be
subjected to thermal melt molding [Cf. "Plastic No Jiten (Plastic
Dictionary)", page 836-838, published by Asakura Shoten, Mar. 1,
1992]. Accordingly, a film of PTFE is obtained by compression
molding to give a sheet, by shaping in a block and cutting or
slicing the block to give a relatively thick sheet or by skiving
working to give a thinner film.
The skiving method will further be illustrated in detail. A
suitable amount of a powdered resin raw material for shaping
working, obtained by suspension polymerization to give a grain
diameter of .about.10 .mu.m, is charged in a metallic mold for
sintering shaping, previously shaped at room temperature and at a
pressure of 100 to 1000 kg/cm.sup.2 in a compression press and then
sintered at 360 to 380.degree. C. for several hours ordinarily but
depending on the size of a shaped product. Then, the metallic mold
is cooled at normal pressure or at some pressure, thus obtaining a
primary shaped product in the form of a sheet, block or cylinder.
The shaped product of PTFE in the form of a cylinder, obtained in
the above described compression shaping, is fitted to a lathe and
revolved, during which an edged tool is pressed against the shaped
product at a constant pressure and a specified angle to obtain a
PTFE film with a thickness of 40 to 50 .mu.m and at most 200
.mu.m.
The film prepared by this skiving method has a disadvantage that
there remain pinholes or skiving scratches on the surface thereof
and accordingly, the film is not suitable for laminating a sealing
stopper for preventing it from leaching of rubber components in a
medicament and contaminating the medicament.
On the other hand, a casting method comprising adding a latex
emulsion to a suspension of fine grains of a fluoro resin, thinnly
spreading the mixture on a metallic surface and then burning to
obtain a film has been known as disclosed in U.S. Pat. No.
5,194,335. According to this method, a film with a thickness of up
to about 3 .mu.m can be produced.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a sealing
stopper for a syringe and a prefilled syringe, whereby the above
described problems can he resolved.
It is another object of the present invention to provide a sealing
rubber stopper for a syringe, in which a surface of the rubber body
is laminated with a PTFE film or UHMWPE film, whereby more
sufficient and excellent sealing property and slidable property as
compared with those of the prior art can be given without using
silicone oil.
It is a further object of the present invention to provide a
sealing rubber stopper for a syringe, in which a surface of the
rubber body is laminated with a PTFE film or UHMWPE film, having no
pinholes nor scratches and having high sanitary property.
It is a still further object of the present invention to provide a
prefilled syringe, in which a medicament is enclosed and sealed in
an injection cylinder or two-component cylinder by the use of the
sealing stopper for a syringe.
These objects can be attained by a sealing stopper for a syringe,
in which a surface of the rubber body is laminated with a
tetrafluoroethylene resin film or ultra-high molecular weight
polyethylene film having an average roughness Ra on the central
line of the surface in a range of at most 0.05 .mu.m and a
kinematic friction coefficient of at most 0.2, and a prefilled
syringe, in which a medicament is enclosed and sealed in an
injection cylinder or two-component cylinder by the use of the
sealing stopper for a syringe. A surface of tie rubber body is
laminated with a tetrafluoroethylene resin film or ultra-high
molecular weight polyethylene film having an average roughness Ra
on the central line of the surface in a range of at most 0.05 .mu.m
and a kinematic friction coefficient of at most 0.2.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings are to illustrate the principle and
merits of the present invention in detail.
FIG. 1(a), (b) and (c) are cross-sectional views of structures of a
sealing stopper and prefilled syringe according to the present
invention.
FIG. 2 is a chart with a multiplication of about 60000 times,
showing measured data of surface roughness of a PTFE film obtained
by a casting method used in Example of the present invention and a
PTFE film obtained by a skiving method used in Comparative Example,
for comparison.
FIG. 3(a) to (h) are cross-sectional views of various shapes of the
sealing stoppers according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The inventors have made various studies to develop a sealing
stopper laminated with a PTFE film or UHMWPE film capable of
preventing the rubber body from elution of rubber components and
contamination of a medicament in contact with the rubber stopper.
Accordingly, it is found that the PTFE film or UHMWPE film having
the specified surface roughness and kinematic friction coefficient
is effective for this purpose.
As a means for solving the above described problems, there are
provided the following inventions and embodiments:
(1) A sealing stopper for a syringe, in which a surface of the
rubber body is laminated with a tetrafluoroethylene resin film or
ultra-high molecular weight polyethylene film having an average
roughness Ra on the central line of the surface in a range of at
most 0.05 .mu.m and a kinematic friction coefficient of at most
0.2.
(2) The sealing stopper for a syringe, as described in the above
(1), wherein the tetrafluoroethylene resin film is prepared by a
casting shaping method comprising using, as a raw material, a
suspension containing tetrafluoroethylene resin powder having a
grain diameter of at most 0.01 to 1.0 .mu.m, a dispersing agent and
a solvent.
(3) The sealing stopper for a syringe, as described in the above
(1), wherein the ultra-high molecular weight polyethylene film is
prepared by an inflation shaping method or extrusion shaping
method.
(4) A prefilled syringe, in which a medicament is enclosed and
sealed in an injection cylinder or two-component cylinder by the
use of the sealing stopper for a syringe. A surface of the rubber
body is laminated with a tetrafluoroethylene resin film or
ultrahigh molecular weight polyethylene film having an average
roughness Ra on the central line of the surface in a range of at
most 0.05 .mu.m and a kinematic friction coefficient of at most
0.2.
(5) A process for the production of a sealing stopper for a
syringe, which comprises preparing a suspension of
polytetrafluoroethylene fine grains having a maximum grain diameter
in a range of 0.01 to 1.0 .mu.m with a concentration of 40 to 50%
in a suitable solvent containing a dispersing agent, coating the
resulting suspension onto a metallic belt, and heating and drying
the coating at a temperature of higher than the melting point of
polytetrafluoroethylene to form a thin film. This procedure is to
obtain a sintered cast film with a suitable thickness and then
laminating a rubber body with the cast film.
(6) The process for the production of a sealing stopper for a
syringe, as described in the above (5), wherein the thin film has a
thickness of 5 to 20 .mu.m and the sintered cast film has a
thickness of 10 to 60 .mu.m.
Referring to FIG. 1 showing a sealing stopper for a syringe (which
will hereinafter be referred to as "sealing stopper") and a
prefilled syringe of the present invention, a sealing stopper 1
shown in FIG. 1(a) comprises a rubber stopper body 2 whose surface
is laminated with a resin film 3. 4 designates a fitting part of a
plunger not shown. In a formulation step for an injection
medicament, the end of an injection cylinder 5 shown in FIG. 1 (b)
is sealed by a cap 6, and an injection medicament 7 is charged for
the formulation in an injection cylinder 5, followed by sealing by
the sealing stopper 1 to prepare a prefilled syringe. Ordinarily,
an injection needle, plunger and covers for the various parts (not
shown) are adapted to the prefilled syringe, thus obtaining a
finished product.
The inventors have made various studies and investigations and
consequently, have found that if the resin film 3 laminated on the
surface of the rubber stopper body 2 has the specified surface
property, i.e. a surface roughness represented by an average
roughness Ra on the central line of the surface in a range of at
most 0.05 .mu.m, measured according to JIS B0601-1982, and a
kinematic friction coefficient of at most 0.2, measured according
to JIS K7218-1986, a very high sealing property and slidable
property can be realized. From the standpoint of a resin film
having both the sanitary property and chemical stability required
in the field of the sealing stopper for a syringe and a prefilled
syringe of the present invention, the PTFE film and UHMWPE film are
most suitable. In particular, the PTFE film prepared by a casting
method using the specified raw materials or the UHMWPE film
prepared by the inflation shaping method or extrusion shaping
method is most suitable because of the capability of adjusting the
surface roughness to the scope of the present invention. The
present invention is based on this finding. Thus, a high sealing
property and slidable property (low kinematic friction resistance)
can be obtained to improve the quality holding property of
medicaments and make easy medical operations.
FIG. 1(a), (b) and (c) are schematic views for illustrating a
sealing stopper for a syringe (which will hereinafter be referred
to as "sealing stopper") and prefilled syringe according to the
present invention. As shown in FIG. 1(a), the sealing stopper 1 has
the resin film 3 consisting of PTFE or UHMWPE laminated on the
surface of the rubber stopper body 2. Since the prefilled syringe
of the present invention is also used as a container for an
injection liquid medicament, it is required that a resin film
laminated on a rubber surface not only has physical sealing
property and slidable property, but also it is hardly subject to
adsorbing or elusion even if contacted with a medicament for a long
time and not harmful to the human body.
The reason why PTFE is particularly selected and used from various
fluoro resins in the present invention is that PTFE has such a
stable property that dissolving or swelling does not appear in
substantially all medicaments, PTFE has such an excellent heat
resistance of organic materials that at about 327.degree. C.
(corresponding to the melting point), it becomes only transparent
gel-like and does not show melt flow property, and the continuous
application temperature is very high, i.e. about 260.degree. C., a
PTFE film has a surface excellent in hydrophobic property,
lipophobic property and non-sticky property and PTFE has an
excellent slidable property such as represented by a smaller
kinematic friction coefficient as shown in Table 1 than that of
other plastics. According to these advantages, physical properties
and chemical properties required for a surface laminating film of a
sealing stopper for a syringe can be satisfied because of being
resistant to a sterilizing processing at a high temperature in a
formulation process, being free from adsorption or elusion even if
contacted with a medicament filled inside for a long time and
chemically stable and having such a high slidable property that a
sealing stopper can smoothly be thrusted in a syringe during
administration of a medicament.
Furthermore, the reason why UHMWPE is used as another laminating
film consists in that various polyethylenes, in general, have
chemical stability and high chemical resistance, very high melt
viscosity and good thermal stability. UHMWPE having a molecular
weight of at least one hundred million, in particular, is excellent
in wear resistance, shock resistance and self lubricating property,
has such a small friction coefficient similar to PTFE that it can
preferably be used as a coating resin and is so excellent in
radiation resistance that it can be applied to sterilization by
radiation.
In Table 1 are shown kinematic friction coefficients as a
coefficient for showing the degree of sliding (slidable property)
of PTFE and UHMWPE for comparison with other resins, measured by
JIS K7218-1986.
TABLE 1 ______________________________________ Kinematic Friction
Coefficient Resin (kg/cm.sup.2 .multidot. m/sec)
______________________________________ Polytetrafluoroethylene
(PTFE) 0.2 Ultrahigh Molecular Weight Polyethylene 0.2 (UHMWPE)
Nylon 66 0.4 Polyoxymethylene 0.4
______________________________________
In the present invention, a PTFE film or UHMWPE film having an
average roughness Ra on the central line of the surface in a range
of at most 0.05 .mu.m according to JIS B0601-1982 is used, and the
film capable of satisfying this characteristic value shows a very
smooth surface and allows sufficently to display elasticity of a
rubber stopper.
PTFE or UHMWPE of the present invention can be produced by any one
of production processes capable of giving the specified surface
roughness and kinematic friction coefficient, but since the PTFE
film meets with the problem of pinholes when it is subjected to
slicing or skiving as described above, it is particularly
preferable to employ a casting method capable of providing
excellent surface properties so as to realize the above described
surface roughness.
FIG. 2 is a chart showing measured data of surface roughness of a
PTFE film (D-1) obtained by a casting method used in Reference
Example 1 and a PTFE film (D-2) obtained by a skiving method used
in Reference Example 2 for comparison, respectively measured by JIS
B0601-1982. The, x-direction shows a measured length (unit mm),
y-direction shows a cut-off value (unit mm) and the maximum height
(Rmax) is a height difference between the maximum value and minimun
value, represented with a multiplication of about 60,000 times. As
is evident from FIG. 2, the surface of film D-1 is much smoother
than that of D-2.
UHMWPE having a very high melting point can be formed into a thin
film by a method comprising heating under pressure and skiving a
primary molding in an analogous manner to PTFE as described above
before obtaining a sheet or film or sintering it into a sheet.
Since the skiving method has the above described problem, however,
it is particularly preferable to employ an extrusion method or an
inflation forming method comprising closing one end of a UHMWPE
film formed in a tubular form and blowing compressed air into the
tubular form from the other end thereof to inflate it. Thus,
the
specified surface roughness on the central line of the surface in a
range of at most 0.05 .mu.m according to the present invention is
realized in the similar manner to D-1 except omitting the measured
chart.
As the thickness of a film to be laminated on a rubber stopper body
is thinner, the rubber elasticity can more effectively be utilized
and the sealing property is better, but handling of the film is
difficult during producing and lamination working of the laminated
stopper. Thus, the thickness of the PTFE film or UHMWPE film
according to the present invention is generally about 0.001 mm to
0.1 mm, preferably 0.001 to 0.05 mm, more preferably 0.005 to 0.03
mm. In the real manufacturing, the void ratio is low in the case of
a thickness range of 0.01 to 0.05 mm, the proportion defective
being decreased. Production of a sealing stopper with a laminated
film thickness of at most 0.001 mm is difficult and this is a
critical limit in the lamination working of a rubber stopper body.
On the other hand, a thickness exceeding 1 mm is not preferable
because of not obtaining high sealing property.
Production of a PTFE film by a casting method will specifically be
illustrated. A PTFE suspension is prepared by the use of a suitable
dispersing agent, the suspension having such a grain diameter that
a stable suspended state can be maintained, i.e. a maximum grain
diameter of 0.01 to 1.0 .mu.m, preferably at most 0.5 .mu.m, and a
solid concentration of about 35 to 60%. A more preferred
concentration is about 40 to 50%. As a solvent and dispersing
agent, there can be used commonly used ones. As a dispersant, for
example, there is used a nonionic surfactant such as Nissan Nonion
HS 208 (Commercial Name, manufactured by Nippon Yushi Co., Ltd.).
As a solvent, for example, water can be used. In Table 2 are shown
examples of compositions of the suspensions without limiting the
present invention.
TABLE 2 ______________________________________ Weight (g)/ Resin
Concentration Volume (1) (weight %) Density of Suspension
______________________________________ PTFE 900 60 1.50 Resin 693
50 1.39 601 45 1.34 515 40 1.29 436 35 1.24 Surfactant.sup.1) 1
weight % Solvent.sup.2) 1 liter (total)
______________________________________ (note) .sup.1) Nissan Nonion
HS 208 (Commercial Name, manufactured by Nippon Yushi Co., Ltd.)
.sup.2) water
The suspension is poured onto a high heat resistance, rust proofing
belt, for example, stainless steel belt, heated in a heating
furnace of closed type at a temperature of higher than the melting
point of PTFE (327.degree. C.) to evaporate water content and then
subjected to sintering working for 4 to 6 hours to form a thin
film. Since the feature of this method consists in directly
preparing a thin film without a step of preparing a cylindrical
primary work as in other methods, there can be obtained a thin film
free from pinholes or surface scratches due to the above described
skiving working method. Furthermore, a very fine PTFE with a
maximum grain diameter of at most 1.0 .mu.m is herein used, thus
resulting in a film product with a true specific gravity of
approximately 2.14 to 2.20, which scarcely has pinholes even as a
result of visual observation or pinhole investigation and exhibits
very small surface roughness, i.e. excellent smoothness.
A rubber used for the sealing rubber stopper of the present
invention is not particularly limited, but is exemplified by
synthetic rubbers such as isoprene rubbers, butadiene rubbers,
styrene butadiene rubbers, ethylene propyrene rubbers,
isoprene-isobutylene rubbers, nitrile rubbers, etc. and natural
rubbers. The rubber used as a predominant component can be blended
with additives such as fillers, cross-linking agents, etc. For the
sealing stopper for a prefilled syringe according to the present
invention. However, it is preferable to select a material excellent
in sanitary property as well as in gaseous permeability resistance
so as to stably store a liquid medicament for a long time, e.g. 3
years in a container (injection cylinder). A compounding example of
such a rubber formulation is shown in the following Table 3. When a
PTFE film having a high softening point is laminated, Compounding
Examples 1 and 2 each using a high vulcanization temperature are
suitable, and when a UHMWPE film having a melting point of
135.degree. C. is laminated, Compounding Examples 3 and 4 are
suitable. In the present invention, the shape of the rubber stopper
body and production process thereof are not particularly
limited.
TABLE 3 ______________________________________ Compounding
Composition Example 1 2 3 4 ______________________________________
Butyl Rubber.sup.1) 100 Chlorinated Butyl Rubber.sup.2) 100
Isobutylene-Isoprene-Divinylbenzene 100 Terpolymer Partially
Cross-linked Butyl Rubber.sup.3) Acrylonitrile-Butadiene
Rubber.sup.4) 100 Wet Process Hydrous Silica.sup.5) 35 30 30 20
Dipentamethylene Thiuram 2.5 Tetrasulfide.sup.6) Zinc
Di-n-dibutylthiocarbamate.sup.7) 1.5 Active Zinc Oxide.sup.8) 5 4
1.5 Stearic Acid.sup.9) 1.5 3 Magnesium Oxide.sup.10) 1.5
2-Di-n-butylamino-4,6-dimercapto-s- 1.5 triazine.sup.11)
1,1-Bis(t-butylperoxy)-3,3,5-tri- 2 8 methylcyclohexane.sup.12)
Total (weight part) 145.5 140.0 133.5 128 Vulcanization Conditions
Temperature (.degree. C.) 175 180 150 155 Time (min) 10 10 10 10
______________________________________ (Note): .sup.1) manufactured
by Exxon Chemical Co., Esso Butyl # 365 (commercial name), bonded
isoprene content: 1.5 mol %, Mooney viscosity: 43 to 51 .sup.2)
manufactured by Exxon Chemical Co., Esso Butyl HT 1066 (commercia
name), bonded chlorine content: 1.3 wt %, Mooney viscosity: 34 to
40 .sup.3) manufactured by Bayer AG, Bayer Butyl XL10000
(commercial name) .sup.4) manufactured by Nippon Zeon Co., Nipol DN
102 (commercial name), bonded acrylonitrile content: 42 wt %,
Mooney viscosity: 60 .sup.5) manufactured by Nippon Silica Kogyo
Co., Nipseal ER (commercial name), pH: 7.5 to 9.0 (5% aqueous
solution) .sup.6) manufactured by Kawaguchi Kagaku Kogyo Co., Accel
TRA (commercial name), MP: at least 120.degree. C. .sup.7)
manufactured by Kawaguchi Kagaku Kogyo Co., Accel BZ (commercial
name) .sup.8) manufactured by Seido Kagaku Kogyo Co., Active Zinc
White AZO (commercial name), ZnO 93 to 96% .sup.9) manufactured by
Kao Co., Lunack S# 30, (commercial name) .sup.10) manufactured by
Kyowa Kagaku Kogyo Co., Kyowa Mag # 150 (commercial name), specific
surface area: 130 to 170 mg .sup.11) manufactured by Sankyo Kasei
Co., Jisnet DB (commercial name) MP at least 137.degree. C.
.sup.12) manufactured by Nippon Yushi Co., Perhexa 3M40 (commercial
name) molecular weight: 302, one minute halflife temperature:
149.degree. C.
Lamination of a surface of a rubber stopper with a PTFE film or
UHMWPE film according to the present invention can be carried out
by a known technique, for example, comprising subjecting one side
of a film to a chemical etching treatment, sputtering treatment or
corona discharge treatment, arranging the film in a metallic mold
for shaping with a rubber compound as a base material of a sealing
stopper body and then vulcanizing, or bonding and shaping in a
predetermined shape. FIG. 3 shows various shapes, in cross section,
of sealing stoppers of the present invention without limiting the
same. Even if a syringe has a complicated structure, for example,
in which a plurality of annular projections are formed on a
slidable area of an inner wall of the syringe, the advantages of
the present invention can of course be obtained. An area to be
laminated includes a part in contact with an inner wall of a
syringe or a part in contact with a medicament and is not intended
to be limited thereto.
Since the sealing stopper of the present invention has a very high
slidable property, even if the sealing stopper is designed in such
a size that its compressibility, i.e. sealing property becomes
higher by enlarging a difference between an inner diameter of an
injection cylinder and an outer diameter of the sealing stopper, as
shown in Examples hereinafter described, sufficient slidable
property can be obtained.
The sealing stopper of the present invention can be applied to not
only plastic injection cylinders, but also glass injection
cylinders. However, since glass surfaces generally have larger
roughness than plastic surfaces, the sealing stopper of the present
invention can be applied to the plastic injection cylinders with
better sealing property and sliding property.
The prefilled syringe of the present invention includes any one of
the syringes of prefilled type using the sealing stopper for
syringes according to the present invention hereinbefore
illustrated. There is no limitation concerning materials or shapes
of injection cylinders and other parts, for example, caps at front
ends thereof, plunger rods provided at the back end of the sealing
stopper, etc. For example, as a material for an injection cylinder
(including two-component vessel), there are generally used plastics
from the standpoint of the above described surface roughness, such
as cyclic olefin resins, cyclic olefin-ethylene copolymer,
polyethylene terephthalate resins, polystyrene resins, etc. In
particular, cyclic olefin resins and cyclic olefin-ethylene
copolymer are preferably used because of having higher transparency
and heat resistance and having no chemical interaction with
medicaments.
FIG. 1(c) shows a state of fitting a sealing stopper 1 to an
injection cylinder 5. In the case of a prefilled syringe, a
medicament is previously charged in the injection cylinder 5
serving also as a vessel for storage of an injection agent 7. The
sealing stopper 1 is thrusted therein to close the injection
cylinder to obtain a product. 6 designates a cap for closing an
injection needle-fitted opening at the end of the injection
cylinder 5. The syringe of this type includes the so-called kit
articles. Since the storage period of a medicament generally
extends to a long period of time, i.e. three years, in particular,
sealing property, chemical resistance and chemical stability are
required for the sealing stopper and during use, moreover, higher
slidability and operativeness must be provided for emergency. The
article of the present invention can satisfy all the
requirements.
The present invention will now be illustrated in detail by the
following Examples and Comparative Examples without limiting the
same.
Reference Example 1
Production of PTFE Film (D-1) by Casting Method 6.01 kg of PTFE
fine powder (Hostaflon TF 1760 -commercial name-, manufactured by
Hoechst AG, maximum grain diameter: less than 1 .mu.m, mean grain
diameter: 0.1 .mu.m) was added to 10 liters of Nissan Nonion HS 208
(nonionic surfactant) diluted with distilled water to 6% and
adequately suspended and dispersed by means of a homogenizer to
obtain 16.01 kg of a 45 weight % PTFE suspension. The suspension
was coated onto a cleaned and polished stainless steel plate to
give a coating thickness of 10 .mu.m (generally, 5-20 .mu.m), dried
for 1.5 minutes by an infrared lamp and heated at 360-380.degree.
C. for about 10 minutes to evaporate the surfactant. After
repeating this procedure four times (generally, 1-8 times), the
suspension was sintered in a thickness of about 40 .mu.m (0.04 mm)
(generally, 10-60 .mu.m). After the last sintering, the resulting
layer was quenched with water and stripped from the metal plate to
obtain a clear PTFE casting film (D-1). The number of the
procedures was increased or decreased and thus, a film with a
desired thickness could be obtained.
Reference Example 2
Production of PTFE Film (D-2) by Skiving Method
For comparison, a PTFE film was produced by the skiving method of
the prior art, as described in the column of Prior Art (D-2). The
same PTFE fine powder as that of Reference Example 1 was uniformly
charged in a metallic mold having a diameter of 250 mm and height
of 2000 mm and being of a polished stainless steel sheet, while
passing through a stainless steel sieve of 10 mesh. The fine powder
was gradually compressed to 300 kg/cm.sup.2 at normal temperature
and maintained for 25 minutes to obtain a preformed product, which
was heated to 370.degree. C. at a rate of 10.degree. C./min in an
electric furnace and maintained at this temperature until the whole
material was uniformly sintered. The sintered product was then
cooled to room temperature at a temperature lowering rate of
15.degree. C./min to obtain a sintered article. The thus obtained
sintered round rod (300 mm diameter.times.500 mm h) was subjected
to skiving working, thus obtaining a PTFE film with a thickness of
about 40 .mu.m or a desired thickness.
The surface roughness of thus resulting D-1 and D-2 films and an
ETFE film (D-3) obtained by an extrusion method as Reference
Example 3 was measured by the following measurement method using a
surface roughness and shape measurement device (Surface 550A
-commercial name-, manufactured by Tokyo Seimitsu Co.) at a
magnification of 60000, a cutoff value of 0.5 mm and a measured
length of 4.0 mm, thus obtaining results as shown in Table 4. This
measurement was carried out as to only the film, not after
laminated, since the measurement of the laminated film was
impossible from the structure of the measurement device.
Measurement Method of Roughness Depth on Film Surface
Measurement of the surface roughness was carried out according to
JIS B0601-1982 using the surface roughness and shape measurement
device of needle touch type (Surface 550A). While the needle part
of the measurement device was applied to a surface of a sample and
moved within a predetermined range, an average roughness (Ra) on
the center line, maximum height (Rmax) and ten point average
roughness (Rz) were measured to obtain a measured chart, from which
Ra, Rmax and Rz were read. The measurement was carried out six
times as to each sample and arithmetical average values of Ra, Rmax
and Rz were obtained excluding the maximum value. Ra and Rz values
represented the roughness depths of the film surface by numeral as
an arithmetical average of all the roughness depth profiles
from the center line.
As to each of the foregoing Samples D-1 to D-3, a film of 20 .mu.m
thick was prepared and subjected to measurement of the kinematic
friction factor of the surface according to the following
measurement method. Measured results and properties of the each
film are shown in Table 4.
Measurement Method of Kinematic Friction Factor
The kinematic friction factor is a factor representative of a
degree of sliding (slidability) of a film. According to JIS
K7218-1986, the kinematic friction factor of a surface of a sample
was measured using a friction and abrasion tester of Matsubara type
(manufactured by Toyo Poldwin Co.) under test conditions of
workpiece: SUS, load: 5 kgf-50 kgf (same load for 30 minutes every
5 kgf), speed: 12 m/min, time: 168 hours. Calculation of the
kinematic friction factor was carried out by the following
formula:
Overall Light Percent Transmission and Haze
The overall light percent transmission and haze were measured
according to JIS K7105-1981, "Test Method of Optical Properties of
Plastics" using a device for measuring light transmission of
integrated globe type. The haze means a ratio of scattered light to
a quantity of transmitted light through a sample. The light percent
transmission is a ratio of the overall light transmission and
diffusion transmission to the quantity of the overall projected
light.
TABLE 4
__________________________________________________________________________
Reference Example 1 Reference Example 2 Reference Example 3
Reference Example
__________________________________________________________________________
4 Film No. D-1 D-2 D-3 D-4 Resin: Production PTFE: PTFE: ETFE:
UHMWPE: Process Casting Method Skiving Method Extrusion Method
Inflation Method Central Line Average Roughness: Ra 0.036 .mu.m
0.136 .mu.m 0.03 .mu.m 0.032 .mu.m Maximum Height: Rmax 0.910 .mu.m
0.212 .mu.m 0.87 .mu.m 0.89 .mu.m Ten Point Average Roughness: Rz
0.396 .mu.m 1.290 .mu.m 0.23 .mu.m 0.30 .mu.m Kinematic Friction
Factor 0.07 kg/cm.sup.2 .multidot. m/sec 0.10 kg/cm.sup.2
.multidot. m/sec 0.38 kg/cm.sup.2 .multidot. m/sec 0.20 kg/cm.sup.2
.multidot. m/sec Tensile Strength Length Direction 3.5 kg/mm.sup.2
4.2 kg/mm.sup.2 124 kg/mm.sup.2 45,000 kg/mm.sup.2 Width Direction
3.5 kg/mm.sup.2 2.0 kg/mm.sup.2 118 kg/mm.sup.2 43,500 kg/mm.sup.2
Elongation Length Direction 360% 450% 1057% 350% Width Direction
340% 460% 1273% 340% Overall Light Percent Transmission 92% 88% 99%
55% Haze 33% 82% 1% 38% Heat Shrinkage Length Direction 0.8% 1.5%
0.5% 20% (100.degree. C.) Width Direction 0.7% -1.2% 0.4% 25% Heat
Shrinkage Length Direction 1.8% 2.9% 1.4% MP 135.degree. C.,
(200.degree. C.) Width Direction 1.7% -1.8% 1.2% impossible to
__________________________________________________________________________
measure
Example 1 and Comparative Examples 1 and 2
In the following Example and Comparative Examples, a rubber sheet
having an excellent gas permeability resistance of Compounding
Example 2 in Table 3 was used. According to the compounding
formulation, the mixture was kneaded using an open roll, aged for
24 hours and heated to obtain an unvulcanized rubber sheet. The
resulting rubber sheet and D-1, D-2 and D-3 films with a thickness
of 20 .mu.m, obtained in the foregoing Reference Examples, were
placed on a metallic mold for shaping, corresponding to a
cross-sectional shape of a stopper shown in FIG. 3(a), pressing at
a mold-fastening pressure of 150 kg/cm.sup.2 depending on the
vulcanization conditions of at 150 to 180.degree. C., vulcanized
for 10 minutes, and the whole body of the rubber stopper was
laminated with PTFE or ETFE film to prepare a sealing stopper with
a cross-sectional shape as shown in FIG. 3(a). The size of the
sealing stopper was allowed to correspond to that of an injection
cylinder used in each test described hereinafter.
Measurement of Sliding Resistance Value
Injection cylinders each having a volume of 5 ml and 100 ml, made
of plastic (polypropylene), and sealing stoppers having sizes shown
in Table 5, corresponding to these injection cylinders were
prepared and each of the sealing stoppers was thrusted and set into
the injection cylinder. The sealing stopper was slowly thrusted
therein in such a manner that the end of the sealing stopper
reached a position for defining a specified volume, thus preparing
a sample injection cylinder. Then, a commercially available
disposable injection needle having a determined size was firmly
inserted into the end of the sample injection cylinder. Using a
commercially available syringe fitted with an injection needle, on
the other hand, distilled water with the specified volume of the
injection cylinder was charged in the end of the sample injection
cylinder, during which care was taken so that air was not allowed
to enter therein. The end of the injection cylinder was directed
downwards, inserted in a metallic jig and the sealing stopper was
thrusted into the end side at a rate of 100 mm/sec by a compression
test disk of spherical seat type of a pressure senser-fitted
measurement device [Autograph AG-1KND -commercial name-
manufactured by Shimazu Seisakujo KK], during which a sliding
resistance value was measured. The maximum value was read from the
thus resulting sliding measured chart to define this as the sliding
resistance value. In general, there was a tendency such that a
value at the start of sliding, i.e. static friction resistance
value Ffs was smaller than a value during sliding (kinematic
friction resistance value) Ffd. The results are shown in Table 5,
from which it is evident that in Comparative Example 3 in which
FTFE was laminated, the slidability is too low to measure the
sliding resistance value and it is difficult to set in the
injection cylinder.
TABLE 5
__________________________________________________________________________
Comparative Example 1 Example 2 3 Injection Diameter of PTFE Coated
Seal- PTFE Coated Seal- ETFE Coated Seal- Cylinder Sealing ing
Stopper by ing Stopper by Stopper by Extru- Volume (ml) Stopper
(mm) Casting Method Skiving Method sion Method
__________________________________________________________________________
5 12.89 21.1 N* 20.4 N not measurable 100 32.58 68.8 N 59.3 N not
measurable
__________________________________________________________________________
(Note): *Newton (1 N = 9.8 kg)
Test for Estimation of Sealing Property for Long time
(Alternative Test for Estimation of Presence or Absence of Invasion
of Microorganisms)
Using sealing stoppers of Example 1 and Comparative Examples 2 and
3 each having a size corresponding to an injection cylinder with a
volume of 5 ml, the following procedure was carried out.
A plastic injection cylinder (volume 5 ml) having a cross-sectional
shape shown in FIG. 1(c) was washed and dried, followed by sealing
the end thereof by a rubber cap. Water with a predetermined volume
was then poured therein and each of the above described sealing
stoppers was slowly inserted into the opening part. In the case of
Comparative Example 2, the sealing stopper was forcedly thrusted
therein. The whole weight (initial weight) of the sample cylinder
was precisely weighed and then subjected to storage under an
accelerating condition of a temperature of 40.degree. C. and
relative humidity of 75% for at least 6 months. During each one
month, each sample injection cylinder was taken and the surface
thereof was dried for 30 minutes in a desiccator, followed by
precisely weighing each sample (at least five measurement points).
The resulting data of weight change was treated in a statistical
manner to calculate a regression function, and a numerical value
corresponding to three years is extrapolated in the time term to
estimate and assess the sealing property for a long time after
formulation of a medicament. In order to correspond to the real
formulation, seventy samples were respectively prepared and
investigated as to both plunger fitted- and plunger-free sealing
stoppers.
A reduction curve Y for the time term X of each sample,
Y=-K+.alpha. lnX, obtained by the above described statistical
procedure can be represented in Example 1, as follows:
When fitting a plunger: Y=-1.896+1.087.times.lnX . . . (a)
When not fitting a plunger: Y=-4.200+1.594.times.lnX . . . (b)
When into the time term X of the above described regression
function formulas (a) and (b) are extrapolated two years (17,520
hours) and three years (26,280 hours) to estimate weight reductions
after two years and three years under a normal state of water for
injection in each sample, the weight reductions are 5.27 mg after
two years and 5.71 mg after three years in the case of (a). The
reduction ratios when the initial weight is 100% are 0.11% in two
years and 0.11% in three years. Similarly, the estimated values of
the reduction and reduction ratio in the case of (b) are 6.31 mg
and 0.12% in two years and 6.96 mg and 0.13% in three years.
The similar procedure to that of Example 1 was also carried out as
to Comparative Example 1 (D-2) and Comparative Example 2 (D-3) to
obtain reduction curves, and reductions and reduction ratios after
two years and three years, obtained by extrapolation of the
reduction curves. The results are shown in Table 6.
As shown in Table 6, the sealing property of the film (ETFE) of D-3
is more excellent, but the sealing stopper of Comparative Example 2
having this film laminated is inferior in slidability between the
film and inner wall of the injection cylinder because of a much
higher sliding resistance so that it cannot be put to practical
use. Even when using the same PTFE film, Example 1, in which the
film by the casting method was laminated, is more excellent in
slidable property and sealing property than Comparative Example 1,
in which the film by the skiving method was laminated.
TABLE 6
__________________________________________________________________________
Laminated Resin Reduction Curve Reduction and Reduction and
(Reference Example): (Regression Function) Reduction Ratio
Reduction Ratio Example Production Process Plunger Y = -.alpha. + K
.multidot. lnX After 2 Years After 3 Years
__________________________________________________________________________
Example 1 PTFE (D-1): yes Y = -1.896 + 1.087 lnX 5.27 mg 0.11% 5.71
mg 0.11% Casting Method no Y = -4.200 + 1.594 lnX 6.31 mg 0.12%
6.96 mg 0.13% Comparative PTFE (D-2): yes Y = -6.357 + 3.518 lnX
16.84 mg 0.32% 17.79 mg 0.34% Example 1 Skiving Method no Y =
-6.676 + 3.617 lnX 17.17 mg 0.32% 18.64 mg 0.35% Comparative ETFE
(D-3)
yes Y = -7.379 + 2.683 lnX 10.31 mg 0.19% 11.40 mg 0.22% Example 2
Extrusion Method no Y = -7.214 + 2.658 lnX 10.31 mg 0.19% 11.39 mg
0.21%
__________________________________________________________________________
Example 2
This Example was carried out as to a sealing stopper having an
UHMWPE film laminated within the scope of the present invention,
prepared by the extrusion method, and another sealing stopper
having an UHMWPE film laminated (D-4) in an analogous manner to
Example 1, Comparative Example 1 or 2, thus obtaining similar good
results to Example 1.
From the foregoing tests, it could be confirmed that the present
invention was very excellent in sealing property as well as
slidable property.
Results of various tests effected as a sealing stopper for a
syringe will be shown using the sealing stopper, as a typical
example, of the type of Example 1 using the film of D-1.
Test for Liquid Sealing Property
(a) Dynamic Loading Conditions
Compressing Test according to Notification No. 442 of the Ministry
of Health and Welfare, Standard of Device for Medical Treatment,
"Standard of Disposal Injection Cylinder", Dec. 28, 1970, and
British Standard.
Ten samples of clean plastic injection cylinders each having a
specified volume were prepared, the end (lure part) of the
injection cylinder being sealed by applying a rubber cap thereto.
An aqueous Methylene Blue solution of 0.1 weight/volume %
concentration in only a determined volume was poured in the
injection cylinder. A rubber sealing stopper having a resin film
laminated on the surface thereof according to the present invention
or a comparative rubber stopper was slowly thrusted from the flange
part of the injection cylinder and while turning up the head of the
cylinder, the rubber cap was taken off at the lure part. A plastic
plunger was screwed in a threaded part at the opening side of the
sealing stopper and slowly pushed up upwards in such a manner that
the liquid in the cylinder was not leaked, thus pushing out air in
the end part of the cylinder. A rubber cap was again applied to the
lure part and mounted on a measurement device for pressure test.
After a pressure defined for medical treatment as shown in Table 7
was added for 10 seconds, the injection cylinder was taken off from
the measurement device and an interface between the sealing stopper
and injection cylinder was observed while magnifying ten times to
confirm whether there was a leakage of the above described blue
aqueous Methylene Blue solution through the interface part or not
(Compressing Test 1). The measured results are shown in Table 8,
from which it is apparent that the sealing stopper of the present
invention exhibits no leakage in any size of injection cylinders.
In addition, Table 8 shows simultaneously the compressibility and
sliding resistance of sealing stoppers, which teaches that even a
sealing stopper having a larger compressibility (higher sealing
property) has a higher sliding property.
When a further larger pressure was added to investigate presence or
absence of leakage in addition to the above described defined
Compressing Test (Compressing Test 2), there was found no leakage
as shown in Table 8.
TABLE 7 ______________________________________ Application Volume
for Injection Cylinder Pressure (10 sec.)
______________________________________ General Medical less than 3
ml 4.0 kg/cm.sup.2 Treatment at least 3 ml less than 10 ml 3.5
kg/cm.sup.2 at least 10 ml less than 20 ml 3.0 kg/cm.sup.2 at least
20 ml less than 30 ml 2.5 kg/cm.sup.2 at least 30 ml 2.0
kg/cm.sup.2 Very Small Amount less than 2 ml 5.0 kg/cm.sup.2 at
least 2 ml 4.0 kg/cm.sup.2 Insulin long 5.0 kg/cm.sup.2 short 4.0
kg/cm.sup.2 ______________________________________
TABLE 8
__________________________________________________________________________
Injection Compressing Test 1 Compressing Test 2 Injection Cylinder
Sealing Stopper Sliding Test Test Cylinder Inner Outer Diameter
Compressibility Resistance Pressure Results Pressure Results Volume
(min) Diameter (mm) (mm) (%) (N) (kg/cm.sup.2) (Observation)
(kg/cm.sup.2) (Observation)
__________________________________________________________________________
1 6.8 7.1 4.8 11.4 4.0 no leakage 6.9 no leakage 3 8.7 9.1 4.5 20.7
3.5 no leakage 5.9 no leakage 5 12.4 12.9 3.8 21.1 3.5 no leakage
3.7 no leakage 10 15.0 15.5 3.3 16.3 3.0 no leakage 3.5 no leakage
20 20.0 21.0 2.1 13.5 2.5 no leakage 3.5 no leakage 50 29.5 30.2
2.4 11.9 2.0 no leakage 2.6 no leakage 100 32.2 32.9 1.2 68.1 2.0
no leakage 2.5 no leakage
__________________________________________________________________________
[note Compressibility = [(Stopper Outer Diameter - Cylinder Inner
Diameter)/Stopper Outer Diameter] .times. 100%
Test for Liquid Sealing Property
(b) Accelerated Conditions
Plastic injection cylinders having various volumes ten by ten and
sealing stoppers having sizes corresponding thereto and end caps
ten by ten were prepared. In a plastic injection cylinder whose end
was covered with a cap was poured a 1% aqueous Methylene Blue
solution of a determined volume and then the sealing stopper of the
present invention and the stopper for comparison were slowly
inserted respectively from the opening part of the injection
cylinder. After passage of at least six months under accelerating
conditions of a temperature of 40.degree. C. and a relative
humidity of 75%, it was confirmed by visual observation whether
there was leakage of the above described aqueous Methylene Blue
solution at the interface between the plastic injection cylinder
and sealing stopper. This method was carried out as a test method
for proving that in the case of formulation of a liquid injection
agent through a sterile formulation step, there was no leakage of
the liquid medicament nor invasion of a liquid material from the
outside.
Test for Liquid Sealing Property
(c) Severer Conditions
Each of samples prepared in an analogous manner to the above
described accelerating test was subjected to confirmation of the
presence or absence of leakage of the above described aqueous
Methylene Blue solution at the interface between the plastic
injection cylinder and the sealing stopper by heating at
121.degree. C. for 30 minutes using an autoclave. This method is a
method for estimating a sealing property in a formulation step,
which comprises adding a stress similar to a formulation step of a
part of a liquid injection agent, sterilized after the formulation.
The results of the foregoing (b) and (c) are shown in Table 9.
Gas Sealing Property Test (Invasion of Steam: Test according to
"Moisture Permeability Test of US Pharmacopoeia", 22nd Edition)
Injection Cylinders each having a volume of 1 to 100 ml (ten by
ten) as shown in Table 8 were precisely weighed, a drying agent was
charged in the injection cylinder, maintained standing, in such a
manner that the thickness (height) be 13 mm, and the sealing
stopper was fixed at a scale of the injection cylinder,
representing a specfified volume. As the drying agent, there was
preferably used calcium chloride passing through a 4-mesh sieve,
dried at 110.degree. C. for 1 hour and then cooled in a desiccator.
After precisely weighing the weight (Ti) of each sample, the sample
was preserved at a temperature of 20.degree. C. and a humidity of
75% RH, and after passage of 14 days, the weight (Tf) was precisely
weighed again. An increment of weight for a period of 14 days
(Tf-Ti) was sought. On the other hand, for control, the initial
weight (Ci) and the weight (Cf) after passage of 14 days were
precisely weighed concerning dried glass beads-charged samples
instead of the calcium chloride to obtain the increment of weight
(Cf-Ci) for control for a period of 14 days. When the volume of the
injection cylinder is V, the moisture permeability can be given by
the following formula. The results are shown in Table 9.
TABLE 9 ______________________________________ Injection Liquid
Sealing Liquid Sealing Gas Sealing Pro- Cylinder Property
Test.sup.1) Property Test.sup.2) perty Test.sup.3) Re- Volume (ml)
Results Results sults (mg/day .multidot. 1)
______________________________________ 1 no leakage of MB.sup.4) no
leakage of MB -1 3 no leakage of MB no leakage of MB -1 5 no
leakage of MB no leakage of MB 2 10 no leakage of MB no leakage of
MB 22 20 no leakage of MB no leakage of MB 25 50 no leakage of MB
no leakage of MB 30 100 no leakage of MB no leakage of MB 2.8
______________________________________ (Note) .sup.1) accelerating
condition: 40.degree. C., 75% RH, 6 months .sup.2) severer
condition: 121.degree. C., 1 hour .sup.3) moisture permeability
test: 20.degree. C., 75% RH, 14 days .sup.4) MB: Methylene Blue
In the moisture permeability test, a sealing property to gas
(steam) at a setting part of a plastic injection cylinder and
sealing stopper is estimated, but this test can be considered to be
an alternative test for estimating the possibility of invasion of
microorganisms. The results of the moisture permeability within a
range of -1 to 30 mg/day, liter according to the present invention,
as shown in Table 9, teach very high sealing property.
Substantially similar good results could be obtained in an
estimation test as to the sealing stopper having UHMWPE laminated
in Example 2.
Advantages of the Invention
As illustrated above, according to the present invention, there can
be obtained a sealing stopper for a syringe, which has more
improved slidability as well as sealing property, to such a degree
that even if the compressibility of a rubber stopper is rendered
higher, smooth sliding can be obtained, by laminating a PTFE film
or UHMWPE film with a very excellent surface property. In
particular, the sealing property in a formulation step (high
temperature or pressure condition) as well as the sealing property
during storage for a long time are higher. Moreover, during use,
administration of an injection medicament can be carried out in
easy and rapid manner because of the higher sliding property, so
that requirements in the real medical scenes may be satisfied. The
above described advantages can similarly be obtained in the case of
the prefilled syringe according to the present invention.
* * * * *